Advanced renal cell carcinoma (RCC) is an invariably fatal cancer that will claim over 13,000 lives in the US in 2013. Currently, small-molecule inhibitors that target angiogenesis or nutrient-sensing pathways represent the primary pharmacological interventions for this disease, but these inhibitors only delay tumor progression and are not curative. RCC therefore represents a significant therapeutic challenge. Unlike current small-molecule therapies, the cytokine interferon-gamma (IFN-?) showed the potential to provide lasting remission in several phase I/II trials for metastatic RCC. IFN-?, however, has severe toxic side-effects that have dampened enthusiasm for its use in the clinic. These side-effects arise from two major limitations that require high doses for clinical benefit: (1) RCC cell are largely resistant to IFN-?'s direct tumoricidal effects, and (2) IFN-? has a very short half-lie in circulation, with consequently poor bioavailabity at the tumor. In this proposal, we outline avenues to overcome both these shortcomings. First, we have identified two survival mechanisms that protect RCC cells from IFN-?; in the absence of either mechanism, IFN-? triggers a novel form of programmed necrosis (or necroptosis) in RCC cells. One of these mechanisms (NF-?B) can be disabled by the small molecule FDA-approved agent bortezomib, and bortezomib sensitizes RCC - but not normal - cells to necroptotic death by doses of IFN-? that are easily clinically achievable. Second, we have generated novel IFN-?-antibody fusion antibodies that (1) stabilize IFN-? in serum, and (2) target IFN-? to RCC cells. We expect that the combination of such IFN-? fusions and bortezomib will exert potent tumoricidal activity while greatly minimizing systemic toxicity. In three aims, we will (1) identify the mechanism by which IFN-? activates necroptosis, (2) identify additional targets in the pathway inhibited by bortezomib by identifying how IFN-? activates NF-?B, and (3) combine native IFN-? and IFN-?-antibody fusions with bortezomib in murine models of RCC. The findings from this study are directly applicable to several human cancers in which IFNs have previously shown therapeutic potential.